Piperazides of the lysergic acid series



Patented Mar. 30, 1954 UNITED STATES ATENT OFFICE PIPERAZIDES OF THE LYSERGIC ACID SERIES Arthur Stoll, Arlesheim, and Theodor Petrzilka, Basel, Switzerland, assignors to Sandoz A. G., Basel, Switzerland, a firm- No Drawing. Application July 14, 1952, Serial No. 298,854

Claims priority, application Switzerland July 28, 1951 12 Claims.

The present invention relates to piperazides of the lysergic acid series which are characterized by therapeutic utility, and to a process for the preparation thereof.

Primary objects of the invention are the embodiment of the said therapeutica and the development of an efiicient synthesis for this purpose.

The first of these objects is realized by the provision, according to this invention, of the piperazides corresponding to the formula wherein R1 stands for a lower alkyl or lower hydroxyalkyl group. These piperazides are characterized by excellent sympathicolytic activity and essential freedom from undesired side effects. They may be administered for example orally. The said piperazides thus constitute good substitutes for the generally difficultly available natural products having sympathicolytic activity.

The second of the aforesaid objects is realized as follows:

The appropriate peptide of the lysergic acid series [see Helv. Chim. Acta 33, 108 (1950)] is first reacted with hydrazine (using for example a mixture of methanol and anhydrous hydrazine), then the resulting hydrazide is converted into the azide by means of nitrous acid (for example, with the aid of NaNOz and a dilute acid such as hydrochloric acid), and then the azide is condensed with L,L-1,2-trimethylene-5-isobuty1- piperazine, which has been obtained by reduction of L-leucine-L-prolinelactam [E. Fischer and G. Half, A. 363, 118 (1908)] with LiAlH4,

in accordance with the following reaction scheme:

Example 1 1.86 parts by Weight of dihydro-lysergyl-L- alanyl methyl ester are dissolved in a mixture of 20 parts by volume of methanol and 5 parts by volume of anhydrous hydrazine. After warming on the water bath for a few minutes, the hydrazide begins to crystallize out. Heating is continued for a further hour and the reaction mixture then allowed to stand over night at room temperature (about The precipitated dihydro lysergyl L alanyl hydrazide melts at 303-305".

0.8 part of finely pulverized L-leucine-L- proline lactam is dissolved in 200 parts of absolute ether by stirring; there are added 1.3 parts of pulverized LiAlH4 and the whole is heated under reflux, precautions being taken to exclude moisture. The excess LiAlH4 is destroyed carefully with a small quantity of water .just exceeding sparingly the quantity which is necessary for this operation. The ether solution is dried by an addition of water-free sodium sulfate. Thereupon the filtration takes place and the ether is evaporated. The distillation of the residue at 95-100/12 mm. yields OAApart of L,L-l,2-trimethylene-5-isobutylpiperazine in the form of a water-clear, flexible oil, [a] =l-15 C11H22N2, c 3O7 3 3 Cale. C, 43.13; H, 4.41; N, 17.50%. Found. 42.85 4.41 17.77%.

1.065 parts by weight of dihydro-lysergyl-L- alanyl hydrazide are dissolved in parts by volume of 0.1 N hydrochloric acid and the solution cooled to 0. 33 parts by volume of 0.1 N sodium nitrite solution are then added dropwise, followed by parts by volume of 0.1 N hydrochloric acid solution, stirring well the whole time. The reaction mixture becomes slimy and viscous. It is made alkaline by addition of a previouslycooled aqueous solution of sodium bicarbonate and extracted with cold ethyl acetate. The solution of the azide is dried over sodium sulphate and coupled with 1.55 parts by weight of L,L-1,2- trimethylene-S-isobutyl-piperazine. To this end, the components are allowed to react at 4 for 20 hours and the solution then shaken out with aqueous sodium bicarbonate solution and dried over sodium sulphate. Evaporation to dryness of the ethyl acetate solution leaves a residue of 2.4 parts by weight which is taken up in benzene and chromatographed through a column containing 100 parts by weights of aluminum hydroxide. The first fractions, obtained by elution with benzene, contain the excess piperazine. The subsequent fractions, obtained by elution with chloroform, yield the crude desired product, from which after two recrystallizations from benzene, the desired piperazide is obtained, melting at 133- 135; [al :80 (c:0.2 in pyridine).

It corresponds to the formula:

ll .1 ll

. cooled to 0.

d Example 2 3.2 parts by weight of dihydro-lysergyl-D-ala nyl-methyl ester are dissolved in 250 parts by volume of hot methanol, and the solution treated with 10 parts by volume of anhydrous hydrazine and boiled for 4 hours under reflux. The dihydro -lysergyl-D-alanyl-hydrazide obtained on evaporating the solution to dryness under reduced pressure crystallizes from methanol in the form of short needles melting at 278-280.

1,065 parts by weight of dihydro-lysergyl-D- alanyl-hydrazide are dissolved in 30 parts by volume of 0.1 N hydrochloric acid and the solution 33 parts by volume of 0.1 N sodium nitrite solution are then added dropwise, followed by 45 parts by volume of 0.1 N hydrochloric acid solution, stirring well the whole time. The reaction mixture is made alkaline with aqueous sodium bicarbonate solution and extracted with cold ethyl acetate. The solution of the azide is dried over sodium sulphate and coupled with 1.5 parts by weight of L,L-1,Z-trimethylene-S-isobutyl-piperazine. The components are, for this purpose, allowed to react for 20 hours at 0, and then shaken out with aqueous sodium bicarbonate solution and dried over sodium sulphate. The residue which remains after evaporation to dryness of the ethyl acetate solution is taken up in benzene and chromatographed through a column containing parts by weight of aluminum hydroxide. Elution of the column with chloroform yields the crude dihydrolysergyl-D-alanyl-L,L- 1,2-trimethylene 5 isobutyl-piperazide, which crystallizes from benzene in the form of needles, melting at 168-170 and correspondingto the formula zo nqg :03 in pyridine).

Example 3 1.0 part by weight of dihydro-lysergyl-Di-valylmethyl ester is dissolved in a mixture of 100 parts by volume of methanol and 3 parts by volume of anhydrous hydrazine and the solution boiled for 3 hours under reflux. The solvent is then removed under reduced pressure leaving a residue which, on crystallization from a mixture of one part methanol and three parts water, yields dihydrolysergyl-D-valyl-hydrazide in the form of short needles melting at 290-292.

0.65 part by weight of dihydro-lysergyl-D-valylhydrazide is dissolved in 1'? parts of volume of 0.1 N hydrochloric acid and the cooled solution treated dropwise first with 18 parts by volume of 0.1 N sodium nitrite solution and then with 25 parts by volume of 0.1 N hydrochloric acid, stirring the whole time. The reaction mixture is made alkaline with aqueous sodium bicarbonate solution and extracted with cold ethyl acetate. After the solution of the resulting azide has been dried over sodium sulphate, it is treated with 0.63

5 part by weight of L,L-1,2-trimethy1ene-5-isobutyl-piperazine and allowed to stand overnight at The reaction mixture is then shaken out with aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue is taken up in chloroform and chromatographed through a column containing 40 parts by weight of aluminum hydroxide. The first fractions consist of excess piperazine, while subsequent fractions, also obtained by elution with chloroform, yield an amorphous substance, recrystallization of which from acetone yields dihydrolysergyl-D-valyl-L,L- 1,2trimethylene-isobutylpiperazide in the form of small clusters of crystals melting at 203- 20 i; [a] :50 (c=0.3 in pyridine).

It corresponds to the formula Example 4 0.10 part by weight of dihydro-lysergyl-L- seryl-methyl ester is treated with 0.5 part by volume of anhydrous hydrazine. The ester passes into solution rapidly and the hydrazide begins to separate out as a finely dispersed precipitate. Th mixture is allowed to stand for 30 minutes at room temperature and then diluted with 1 part by volume of water with cooling, after which the solid is filtered off and washed with water. After drying in a desiccator over concentrated sulphuric acid, the thus-obtained hydrazide melts at 248-251".

The hydrazide is then made into a paste with a little water and a few drops of glacial acetic acid, whereupon it passes into solution. After clarifying by filtration, the hydrazide is re-precipitated by the addition of ammonia. The product, which melts at 251253 is dried in high vacuum at 100.

0.74 part by weight of the thus-prepared dihydro-lysergyl-L-sery1-hydrazide is dissolved in 20 parts by volume of 0.1 N hydrochloric acid and the cooled solution treated dropwise with 22 part by volume of 0.1 N sodium nitrite solution followed by 30 parts by volume of 0.1 N hydrochloric acid, stirrin the whole time. After making the solution alkaline by addition of aqueous sodium bicarbonate solution, the azide is extracted with ethyl acetate and the resulting extract dried over sodium sulphate. To this solution, 1.5 parts by weight of L,L-1,2-trimethylene-5-isobutyl-piperazine are added and it is then allowed to stand for 20 hours at 2.

After working up as in the preceding examples, the obtained residue is purified by chromatography using a column containing 80 parts by weight of aluminum hydroxide. Elution with chloroform containing 0.5-1% methanol yields a substance which, recrystallized from ethyl acetate, gives the dihydro-lysergyl-L-seryl-L,L-

1,2-trimethylene-5-isobutyl-piperazide of the formula The product is obtained in the form of clusters of crystals melting at 199200;

[a] =80 (0:0.3 in pyridine) Example 5 0.7 part by weight of dihydro-lysergy1-D- seryl-methyl ester is dissolved in 2 parts by vol-- ume of methanol, 0.2 part by volume of hydrazine added, and the mixture heated for a short time on the water bath. After allowin it to stand overnight at room temperature, the bulky mass of crystals is filtered off, washed thoroughly with methanol and then dried in a desiccator over concentrated sulphuric acid. In this way, the hydrazide, melting at 249 (in vacuo), is obtained. The product is practically insoluble in most organic solvents and in water.

1.05 parts by weight of dihydro-lysergyl-D seryl-hydrazide are dissolved in 30 parts by volume of 0.1 N hydrochloric acid and to the cooled solution are added dropwise 31 parts by volume of 0.1 sodium nitrite solution followed by 42 parts by volume of 0.1 N hydrochloric acid, with continuous stirring. After making alkaline with, aqueous sodium bicarbonate solution, the resulting azide is extracted with ethyl acetate and the solution dried over sodium sulphate. It is thencoupled at 2 with 0.82 part by weight of L,L-1,2- trimethylene-5-isobutyl-piperazine.

After working up as in the preceding exam ples, the residue is purified by chromatography using a column containing parts by weight of aluminum hydroxide. Elution with chloroform containing 0.5-1% methanol yields a con-- densation product which is recrystallized from acetone to give dihydro-lysergyl-D-seryl-L,L- 1,2 trimethylene 5 isobutyl piperazide. This separated in the form of short needles melting at 203404";

[a] =84 (0:03 in pyridine) Havin thus disclosed the invention what .is claimed is:

1. A process for the preparation of a dihydrolysergyl L,L 1,2 trimethylene 5 isobutyl-piperazide from a peptide of the formula l R-CO.NH.CH

COOCHz wherein RCO. stands for the acyl radical of dihydrolysergic acid and R1 stands for a member selected from the group consisting of lower alkyl and lower hydroxyalkyl, which comprises converting the said peptide by treatment with hydrazine into the corresponding hydrazide and then by reacting with nitrous acid into the azide of the formula and reacting the latter with L,L-1,2-trimethy1- ene-5-isobutyl-piperazine.

2. A process for the preparation of. dihydrolysergyl L alanyl L,L 1,2 trimethylene- 5-isobutyi-piperazide, which comprises converting dihydrolysergyl-L-alanyl-methyl ester by treatment with hydrazine into the corresponding hydrazide and then by reacting with nitrous acid acid into the corresponding azide and reacting the latter with L,L-1,2-trimethy1ene-5-isobuty1- piperazide.

4. A process for the preparation of dihydrolyserg'yl D valyl- L,L 1,2 trimethylene 5- isobutyl-piperazide, which comprises converting dihydrolysergyl-D-valyl-methy1 ester by treatment with hydrazine into the correspondin hydrazide and then by reacting with nitrous acid into the corresponding azide and reacting the latter with L,L-L2-trimethy1ene5-isobuty1-piperazide.

5. A process for the preparation'of dihydro lysergyl L seryl L;L 1,2 trimethylene 5'- isobutyl pipera'z'ide, which comprises converting dihydrolysergyl L'-sery1-methyl ester by treatment with hydrazine into the corresponding hy-'- drazide and then'by reacting with nitrous acid into the corresponding azide and reacting the latter with L,L-1,2 trimethylene-5-isobutyl piperazine'.

6. A process for the preparation of dihydrolysergyl D seryl L,L 1,2 trimethylene 5- isobutyl-pip'erazide, which comprises converting dihydrolysergyl-D-seryl-methyl ester by treatment with hydrazine into the corresponding hydrazide and then by reacting with nitrous acid into the corresponding a'z'i de and reactin the latter with L,L-'1',2-trimethylene-5 isobutyl-piperazine.

7. A compound of the formula wherein R1 stands for a member selected from the group consisting of lower alkyl and lower hydroxyalkyl.

8. Dihydrolysergyl L alanyl L,L 1',2- trimethy1ene-5-isobutyl-piperazide.

9. Dihydrolyserg-yl D alanyl L,L 1,2- trimethylene-S-isobutyl-piperazide. v

10. Dihydrolysergyl D valyl i L,L 1,2 trimethylene-5-isobuty1-piperazide.

11. Dihydrolysergyl L seryl L,L 1,-2 trimethylene-5-isobutyl piperazide.

12. Dihydrolysergy1-- D"'- seryl L,L 1,2 tri methylene-5-isobutyl-piperazide.

ARTHUR STOLL; THEODOR PETRZILKA.

No references cited. 

1. A PROCESS FOR THE PREPARATION OF A DIHYDROLYSERGL -L,L - 1,2 - TRIMETHYLENE -5- ISOBUTYL-PIPERAZIDE FROM A PEPTIDE OF THE FORMULA
 7. A COMPOUND OF THE FORMULA 